Among the more than 20 histocompatibility H2-like genes in the Balb/c mouse genome, there are two classical transplantation antigens (H-2D and H-2L) encoded at the D-end of the major histocompatibility complex. We have identified two bacteriophage clones that encode for H-2D and H-2L. The two genes were identified by nucleotide sequence analysis and by characterization of the new H-2 antigens expressed when the cloned genes were introduced into mouse L cells by DNA-mediated gene transfer. The two genes were compared to each other. The genes appear to have the same general structure, and for the 854 nucleotides that have been compared, the two genes are 89% homologous. The H-2L and H-2D antigens expressed on mouse L cells after DNA-mediated gene transfer were examined by immunologic criteria. The stably transformed L cell lines express apparently normal levels of H-2L and H-2D on the cell surface as measured by quantitative immunofluoresence by using monoclonal anti-H2 antibodies. They evoke a strong specific serologic response when used to immunize C3H mice. The newly expressed antigens are able to serve as targets for alloreactive T cells. Recently we have also started to search for restriction fragment length polymorphisms using probes for genes clustered around the human HLA genes on chromosome 6. Our aim is to use this approach in specific human diseases where there is either an association with an HLA haplotype or a Mendelian inheritance pattern or both. Experiments are now in progress on patients with systemic lupus erythematosus (SLE) and members of their families.